DATA EXTRACTION: One investigator extracted data with review by a second investigator. Investigators independently assessed the risk of bias and strength of evidence (SOE) (ie, confidence in the estimate of effects).

RESULTS: Nineteen randomized controlled trials (RCTs), 4 with a low risk of bias, evaluated supplements or variations of the gluten/casein-free diet and other dietary approaches. Populations, interventions, and outcomes varied. Ω-3 supplementation did not affect challenging behaviors and was associated with minimal harms (low SOE). Two RCTs of different digestive enzymes reported mixed effects on symptom severity (insufficient SOE). Studies of other supplements (methyl B12, levocarnitine) reported some improvements in symptom severity (insufficient SOE). Studies evaluating gluten/casein-free diets reported some parent-rated improvements in communication and challenging behaviors; however, data were inadequate to make conclusions about the body of evidence (insufficient SOE). Studies of gluten- or casein-containing challenge foods reported no effects on behavior or gastrointestinal symptoms with challenge foods (insufficient SOE); 1 RCT reported no effects of camel’s milk on ASD severity (insufficient SOE). Harms were disparate.

LIMITATIONS: Studies were small and short-term, and there were few fully categorized populations or concomitant interventions.

CONCLUSIONS: There is little evidence to support the use of nutritional supplements or dietary therapies for children with ASD.

“The reason fat people are happy is that their nerves are well protected.”– Luciano Pavarotti

It is not uncommon to see kids with behavioral problems that are also obese. Many times, medications which help improve behavioral problems may contribute to obesity by increasing appetite.

A recent study (K Shedlock et al. J Pediatr 2016; 178: 183-7) provides some insight into this issue. In this retrospective study, using the Military Health System database (2000-2013) with 48,762 individuals with autism spectrum disorder and with 243,810 matched controls, children with autism spectrum disorder (ASD) had significantly higher rates of obesity with OR 1.85 along with obesity-related conditions. These conditions include type 2 diabetes, hypertension, hyperlipidemia, and NAFLD/NASH.

Key points:

In children with ASD, mood stabilizers, antipsychotics, antiepileptic drugs, and selective serotonin reuptake inhibitors (SSRIs) were associated with obesity. Mood stabilizers had the greatest risk in this study, with adjusted OR of 1.41; the other medications had fairly small risk with adjusted ORs between 1.13 to 1.16.

When kids with ASD develop complications like NAFLD/NASH or hyperlipidemia, they may be less likely to adhere with recommended lifestyle changes. This can be due to sensory aversions and social deficits.

My take: Children with autism spectrum disorder are likely at increased risk for obesity at baseline; some of the medications to treat behavior problems may contribute to obesity, though they may be partly an epiphenomenon or a marker of a more severe autism spectrum disorder.

There has been a lot of concern that abnormal GI function contributes to both behavioral and gastrointestinal symptoms in children with autism. To categorize some of these problems, the term ‘leaky gut’ has been used.

According to the authors, all of the study subjects underwent endoscopy and “all hadclinical indicationsfor diagnostic endoscopy.” Most common indications were parental reports of abdominal pain and diarrhea.

Key findings:

Disaccharidase activity levels were not significantly different between the groups. In agreement with prior studies, there was frequent lactase deficiency, with 66% of ASD children in this study with deficient enzyme activity (<15 μmol/min/g). However, lactase activity in the children with ASD was not lower than the non-ASD children.

There were no significant differences in measures of intestinal permeability. Normative values for lactulose and rhamnose ratio are not definitively established. However, when using similar cutoff ratios, there were similar results in both groups.

Calprotectin:

Intestinal inflammatory markers (calprotectin/lactoferrin) were not significantly different, after the authors excluded the five “neurotypical” children who were diagnosed with inflammatory bowel disease.

For calprotectin, the authors considered a level <50 mcg/g to be normal. In the ASD group, 31of 49 (63%) had abnormal calprotectin compared with 19 of 31 (61%) in the non-ASD group.

For calprotectin levels >150 mcg/g, 9 of 49 (18%) reached this level in the ASD group and 8 of 31 (26%) in the non-ASD group.

Histology:

Similar levels of GI tract inflammation were noted in both groups –generally mild.

In the ASD group, 32 (52%) had inflammation somewhere in their GI tract, “but it was generally mild and non-diagnostic.” In the ASD group, five had features consistent with GERD, two had eosinophilic esophagitis (EoE). There were 12 (19%) who had colonic inflammation and 3 (5%) with ileal inflammation. None had celiac disease or H pylori.

In the non-ASD group, four had EoE, four (8%) had ileal inflammation, and nine (18%) had colonic inflammation. The authors noted Crohn’s disease in three and a total of five children with IBD.

My take:

This study suggests that symptomatic children with autism have similar (and probably not worse) GI problems as neurotypical children. The idea that children with autism have a more leaky gut than children without autism is quite dubious based on these results.

The biggest problem for GI physicians is not addressed in this study and involves children with and without autism:appropriate selection for evaluation. While the authors chose children with “clinical indications,” these, in fact, are often subjective and with permissive interpretation could be used to justify endoscopy in 40% of children.

Another huge problem is interpretation of abnormal results. While the authors report large numbers with intestinal inflammation in both groups, most of this was considered to be insignificant clinically. How should trivial inflammation be reported in studies? This problem is not unique to this study and makes it difficult to assess the value of endoscopy more broadly.

Based on false science, many parents think that refusing or delaying vaccinations will be safer for their children and decrease the risk of autism. While the scientific underpinnings for such a concept have no basis (Pediatrics 2004; 114: 793-804, and Institute of Medicine. Immunization safety review: vaccines and autism. Washington, DC: National Academies Press; 2004), lingering concerns persist. Into this background, another rigorous study (J Pediatr 2013; 163: 561-7) has concluded that there is “no association between exposure to antigens from vaccines during infancy and the development of autism spectrum disorder (ASD),” autism, or ASD with regression.

So how did the authors reach this conclusion?

Using a case-control study from three managed care organizations (MCOs) of 256 children with ASD and 752 control children, the authors examined exposure to total antibody stimulating proteins and polysaccharides from vaccines. They utilized vaccine registries and medical records. The children in this study were born between 1994-1999 and were aged 6-13 years at the time of data collection.

The results showed that with each 25-unit increase in total antigen exposure, the adjusted odds ratio (aOR) for ASD was 0.999 for cumulative exposure to age 3 months. The aOR stayed the same at 7 months and 2 years. When autism or autism with regression were examined, similarly there was no increased risk.

One of the strengths of this study was that members of these MCOs have routine immunizations as a covered benefit; this helps minimize socioeconomic factors which could influence results. A small number of ASD cases (5%) and controls (2%) had an older sibling with autism; results were unchanged when these children were excluded.

In many ways, this finding is completely anticipated and in agreement with the Institute of Medicines most recent 2013 report on immunizations (The Childhood Immunization Schedule and Safety: Stakeholder…). As the authors note in their discussion, “beginning at birth, an infant is exposed to hundreds of viruses and other antigens, and it has been estimated that an infant theoretically could respond to thousands of vaccines at once.”

Bottom-line: Vaccines prevent disease without causing autism. Vaccine refusal increases the risk of disease for those who refuse and creates collateral damage as well.